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The design of a hybrid one-pot tandem protocol through the combination of biodeoximations (promoted by laccase from Trametes versicolor) and s-block polar organometallics (RLi/RMgX) in aqueous media, at room temperature and under air is reported.

Owing to a growing awareness towards environmental impact, the search for "greener", safer, and cost-effective solvents able to replace petroleum-derived solvents has never been greater today. In this context, the use of environmentally responsible solvents like water and the so-called deep eutectic solvents (DESs), constructed from bio-based compounds, has recently experienced important growth in several fields of sciences. This short review highlights the key features of the chemistry of water and (hydrated) DESs when applied to metal- and biocatalyzed transformations as well as to the synthesis of active pharmaceutical ingredients (APIs) and other biologically relevant compounds by providing, through discussion of all relevant literature over the past five years, a comparison of the outcomes of the reactions when carried out in one or the other solvent.

Deep Eutectic Solvents (DESs) have been widely used in many fields to exploit their ecofriendly characteristics, from green synthetic procedures to environmentally benign industrial methods. In contrast, their application in emerging solar technologies, where the abundant and clean solar energy is used to properly respond to most important societal needs, is still relatively scarce. This represents a strong limitation since many solar devices make use of polluting or toxic components, thus seriously hampering their eco-friendly nature. Herein, we review the literature, mainly published in the last few years, on the use of DESs in representative solar technologies, from solar plants to last generation photovoltaics, featuring not only their passive role as green solvents, but also their active behavior arising from their peculiar chemical nature. This collection highlights the increasing and valuable role played by DESs in solar technologies, in the fulfillment of green chemistry requirements and for performance enhancement, in particular in terms of long-term temporal stability.

Dimethindene is a selective histamine H1 antagonist and is commercially available as a racemate. Upon analyzing the synthetic pathways currently available for the industrial preparation of dimethindene, we set up a sustainable approach for the synthesis of this drug, switching from petroleum-based volatile organic compounds (VOCs) to eco-friendly solvents, such as 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME) belonging to classes 3 and 2, respectively. Beyond decreasing the environmental impact of the synthesis (E-factor: 24.1–54.9 with VOCs; 12.2–22.1 with 2-MeTHF or CPME), this switch also improved the overall yield of the process (from 10% with VOCs to 21–22% with 2-MeTHF or CPME) and remarkably simplified the manual operations, working under milder conditions. Typical metrics applied at the first and second pass, according to the CHEM21 metrics toolkit, were also calculated for the whole synthetic procedure of dimethindene, and the results were compared with those of the classical procedure.

An efficient and selective N-functionalization of amides is first reported via a CuI-catalyzed Goldberg-type C–N coupling reaction between aryl iodides and primary/secondary amides run either in Deep Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction conditions (absence of protecting atmosphere). Higher activities were observed in an aqueous medium, though the employment of DESs expanded and improved the scope of the reaction to include also aliphatic amides. Additional valuable features of the reported protocol include: (i) the possibility to scale up the reaction without any erosion of the yield/reaction time; (ii) the recyclability of both the catalyst and the eutectic solvent up to 4 consecutive runs; and (iii) the feasibility of the proposed catalytic system for the synthesis of biologically active molecules.

A series of multi-target-directed ligands (MTDLs), obtained by attachment of a hydroxyphenylbenzimidazole (BIM) unit to donepezil (DNP) active mimetic moiety (benzyl-piperidine/-piperazine) was designed, synthesized, and evaluated as potential anti-Alzheimer&rsquo, s disease (AD) drugs in terms of biological activity (inhibition of acetylcholinesterase (AChE) and &beta, &ndash, amyloid (A&beta, ) aggregation), metal chelation, and neuroprotection capacity. Among the DNP-BIM hybrids studied herein, the structural isomerization did not significantly improve the biological properties, while some substitutions, namely fluorine atom in each moiety or the methoxy group in the benzyl ring, evidenced higher cholinergic AChE activity. All the compounds are able to chelate Cu and Zn metal ions through their bidentate BIM moieties, but compound 5, containing a three-dentate chelating unit, is the strongest Cu(II) chelator. Concerning the viability on neuroblastoma cells, compounds 9 and 10 displayed the highest reduction of A&beta, induced cell toxicity. In silico calculations of some pharmacokinetic descriptors indicate that all the compounds but the nitro derivatives have good potential oral-bioavailability. Overall, it can be concluded that most of the studied DNP-BIM conjugates showed quite good anti-AD properties, therefore deserving to be considered in further studies with the aim of understanding and treating AD.

An unsubstituted 2-hydroxyphenylbenzimidazole has recently been included as a scaffold in a series of hybrids (including the hit compound PZ1) based on the framework of the acetylcholinesterase (AChE) inhibitor Donepezil, which is a new promising multi-target ligand in Alzheimer&rsquo, s disease (AD) treatment. Building upon these findings, we have now designed and completed the whole synthesis of PZ1 in the so-called deep eutectic solvents (DESs), which have emerged as an unconventional class of bio-renewable reaction media in green synthesis. Under optimized reaction conditions, the preparation of a series of 2-hydroxyphenylbenzimidazole-based nuclei has also been perfected in DESs, and comparison with other routes which employ toxic and volatile organic solvents (VOCs) provided. The functionalization of the aromatic ring can have implications on some important biological properties of the described derivatives and will be the subject of future studies of structure-activity relationships (SARs).

In this contribution, the first direct and efficient functionalization of the preformed 2-phenyltetrahydropyran (2-PhTHP) nucleus by electrophilic interception of the corresponding alpha-lithiated derivative by employing sBuLi as the base and THF as the solvent at -78 degrees C was explored. The presence of N,N,N',N'-tetramethylethylenediamine (TMEDA) proved to be critical to governing reaction feasibility both in polar and apolar solvents and for improving the yield of the reaction. Both carbon-and heteroatom-based halides were found to be competent electrophiles for this transformation, as well as aliphatic and aromatic aldehydes and ketones, isocyanates, and carboxylic acid derivatives. The combination of hexane/TMEDA lowered the rate of racemization of a-lithiated optically active 2-PhTHP, which thereby enabled calculation of its barrier to inversion at -78 degrees C.

International audience; Oxetanes are key synthons for asymmetric synthesis and also effective in directing ortho‐lithiation. This work first reports the solution and the solid‐state structure of an ortho‐lithiated aryloxetane (1‐Li) in the presence/absence of a bidentate ligand such as N,N,N′,N′‐tetramethylethylenediamine (TMEDA). Single crystal X‐ray diffraction analysis of 1‐Li revealed a singular crystallographic structure in which the asymmetric unit comprises a core where the lithium atom is coordinated to the nitrogen atom of half a molecule of TMEDA and intramolecularly stabilised by the oxetane ring oxygen. This aggregation state is unprecedented in ortho‐lithiated arenes. Variable temperatures multinuclear magnetic resonance (1H, 7Li, 13C) mono‐ and two‐dimensional NMR studies and DFT computations supported the coexistence in solution of three chelated bridged dimeric aggregates, in slow equilibration at 180 K. The major isomer is an heterochiral aggregate on the basis of 1H,7Li‐HOESY and 1H,1H‐NOESY experiments. Conclusions were supported by the preparation of enantiomerically enriched (S)‐1‐Li. The privileged formation of homochiral aggregates from racemic mixtures may also have implications for the development of chiral resolution processes.

A Deep Eutectic Solvent like choline chloride/glycerol (1:2 mol mol–1) proved to be an effective, sustainable reaction medium to easily synthesize both phenacyl azides and symmetrical 2,5-diarylpyrazines of interest in pharmacology and in coordination chemistry. Notable features of our report include: (i) nucleophilic substitution reactions of α-halo carbonyl compounds to the corresponding phenacyl azides compatible with the eutectic mixture, (ii) the reduction of phenacyl azides to α-amino carbonyl compounds, which undergo spontaneous dimerisation/cyclisation/aromatisation in the same eutectic mixture to provide valuable pyrazines. Telescoped, one-pot, two-steps stoichiometric/catalytic processes have also been successfully developed to furnish 2,5-diarylpyrazines in up to 95 % yield.

A few symptomatic drugs are currently available for Alzheimer&rsquo, s Disease (AD) therapy, but these molecules are only able to temporary improve the cognitive capacity of the patients if administered in the first stages of the pathology. Recently, important advances have been achieved about the knowledge of this complex condition, which is now considered a multi-factorial disease. Researchers are, thus, more oriented toward the preparation of molecules being able to contemporaneously act on different pathological features. To date, the inhibition of acetylcholinesterase (AChE) and of &beta, amyloid (A&beta, ) aggregation as well as the antioxidant activity and the removal and/or redistribution of metal ions at the level of the nervous system are the most common investigated targets for the treatment of AD. Since many natural compounds show multiple biological properties, a series of secondary metabolites of plants or fungi with suitable structural characteristics have been selected and assayed in order to evaluate their potential role in the preparation of multi-target agents. Out of six compounds evaluated, 1 showed the best activity as an antioxidant (EC50 = 2.6 &plusmn, 0.2 &mu, mol/&micro, mol of DPPH) while compound 2 proved to be effective in the inhibition of AChE (IC50 = 6.86 &plusmn, 0.67 &mu, M) and A&beta, 1&ndash, 40 aggregation (IC50 = 74 &plusmn, 1 &mu, M). Furthermore, compound 6 inhibited BChE (IC50 = 1.75 &plusmn, 0.59 &mu, M) with a good selectivity toward AChE (IC50 = 86.0 &plusmn, 15.0 &mu, M). Moreover, preliminary tests on metal chelation suggested a possible interaction between compounds 1, 3 and 4 and copper (II). Molecules with the best multi-target profiles will be used as starting hit compounds to appropriately address future studies of Structure-Activity Relationships (SARs).

Regio- and stereo-selective reduction of substituted 1,3-aryldiketones, investigated in the presence of different whole cell microorganisms, was found to afford β-hydroxyketones or 1,3-diols in very good yields (up to 95%) and enantiomeric excesses (up to 96%). The enantiomerically enriched aldols, obtained with the opposite stereo-preference by baker's yeast and Lactobacillus reuteri DSM 20016 bioreduction, could then be diastereoselectively transformed into optically active syn- or anti-1,3-diols by a careful choice of the chemical reducing agent (diastereomeric ratio up to 98 : 2). The latter, in turn, were stereospecifically cyclized into the corresponding oxetanes in 43-98% yields and in up to 94% ee, thereby giving a diverse selection of stereo-defined 2,4-disubstituted aryloxetanes.

Developing new green solvents in designing chemical products and processes or successfully employing the already existing ones is one of the key subjects in green chemistry and is especially important in organometallic chemistry, which is an interdisciplinary field. Can we advantageously also use unconventional reaction media in place of current harsh organic solvents for polar organometallic compounds? This microreview critically analyses the state of the art with regard to this topic and showcases recent developments and breakthroughs that are becoming new research directions in this field. Because metals cover a vast swath of the Periodic Table the content is organised into three sections discussing the reactivity of organometallic compounds of s-, p- and d-block elements in unconventional solvents.

Biocatalytic processes are increasingly playing a key role in the development of sustainable asymmetric syntheses, which are central to pharmaceutical companies for the production of chiral enantiopure drugs. This work describes a simple and economically viable chemoenzymatic process for the production of (S)-rivastigmine, which is an important drug for the treatment of mild to moderate dementia of the Alzheimer’s type. The described protocol involves the R-regioselective bioreduction of an aromatic ketone by Lactobacillus reuteri DSM 20016 whole cells in phosphate buffered saline (PBS) (37 °C, 24 h) as a key step. Biocatalytic performance of baker’s yeast whole cells in water and in aqueous eutectic mixtures have been evaluated and discussed as well. The route is scalable, environmentally friendly, and the target drug is obtained via four steps in overall 78% yield and 98% ee.

The presence of an electron-donating methoxy group at the 4′-position of 4-phenyl-3,5-dimethyl-1,2,4-triazole is beneficial to lateral metalation/functionalization of this ring system once sBuLi is employed as the base and THF is used as the solvent at –78 °C; this opens up an alternative approach towards the synthesis of several 1,2,4-triazole derivatives. Both carbon- and heteroatom-based halides are competent electrophiles for this transformation, as are aliphatic and aromatic aldehydes and ketones, isocyanates, carboxylic acid derivatives, and α,β-unsaturated carbonyl compounds. The easy elaboration of such a group to phenol derivatives also provides greater flexibility in synthetic design.

This Microreview focuses on the regio- and stereoselective lithiation of small-ring heterocycles such as aryl-substituted oxiranes, aziridines, azetidines, oxetanes, and tetrahydrofurans highlighting some useful selected synthetic applications extracted from recent literature. It will be shown, in particular, that regio- and stereoselectivity and the configurational stability of the above lithiated species are controlled by a subtle interplay of factors. Aggregation, complexation phenomena, dynamics at the heteroatom of the heterocyclic ring, substitution in both the aryl and the heterocyclic ring, solvent polarity, temperature, and ligands play a crucial role. The ability of the afore-mentioned heterocycles as important directed metalation groups for the arene ortho-functionalization is also discussed as well as the carbene-like nature exhibited by some lithiated epoxides and aziridines.

An unprecedented, environmentally friendly, and faster method for the determination of Ochratoxin A (OTA) (a mycotoxin produced by several species of Aspergillus and Penicillium and largely widespread in nature, in wheat and derived products) has, for the first time, been set up and validated using choline chloride (ChCl)-based deep eutectic solvents (DESs) (e.g., ChCl/glycerol (1:2) and ChCl/ urea (1:2) up to 40% (w/w) water) as privileged, green, and biodegradable extraction solvents. This also reduces worker exposure to toxic chemicals. Results are comparable to those obtained using conventional, hazardous and volatile organic solvents (VOCs) typical of the standard and official methods. OTA recovery from spiked durum wheat samples, in particular, was to up to 89% versus 93% using the traditional acetonitrile-water mixture with a repeatability of the results (RSDr) of 7%. Compatibility of the DES mixture with the antibodies of the immunoaffinity column was excellent as it was able to retain up to 96% of the OTA. Recovery and repeatability for durum wheat, bread crumbs, and biscuits proved to be within the specifications required by the current European Commission (EC) regulation. Good results in terms of accuracy and precision were achieved with mean recoveries between 70% (durum wheat) and 88% (bread crumbs) and an RSDr between 2% (biscuits) and 7% (bread).

The ortho lithiation-trapping sequence of phenylaziridines is described. This methodology, which counts on the ability of the aziridino group to act as a directed metalation group (DMG), provides an easy access to functionalized arylaziridines as well as to phthalans and phthalides. The importance of the aziridine N-substituent in this DoM reaction is stressed as well. [reaction: see text]

[reaction: see text] The stereoselective synthesis of novel alpha-epoxy-beta-amino acids is described by a route that combines the chemistry of oxazolinyloxiranyllithiums with that of nitrones. The intermediate trioxadiazadispiro[2.0.4.3]undecanes 4 have been isolated and converted by hydrolysis into epoxy-5-isoxazolidinones 5 which can be transformed into the alpha-epoxy-beta-amino acids 8 by N-O reduction.

Stereospecific β-lithiation of β-aryl-substituted oxazolinyloxiranes is described. The trapping reaction of such reactive intermediates with carbonyl compounds gave α,β-epoxy-γ-butyrolactones after deblocking of the oxazoline moiety. This methodology has been also extended to the synthesis of optically active α,β-epoxy-γ-butyrolactones.

Several allyl heteroarylalkyl ethers have been synthesized and then deprotonated with nBuLi in THF at −78°C to give lithium derivatives. The lithium-bearing terminus was either the α- or the α′-carbon atom, depending on the associated proton acidity. In the absence of an external electrophile, a sigmatropic rearrangement occurs, generating a new C−C bond. Heteroarylalkyl homoallylic alcohols and allyl heteroarylalkylic alcohols were obtained as products of stereoselective [2,3]- or [1,2]-Wittig rearrangements, respectively. Homoallylic alcohols were obtained in high yields and with fairly good enantiomeric enrichments when the reactions were carried out in toluene with (−)-sparteine as the external chiral ligand.

The two geometric isomers of 2-(tert-butyl)-4-phenyloxetane have, for the first time, been prepared starting from the commercially available 4,4-dimethyl-1-phenylpentane-1,3-dione. The latter was reduced with NaBH4 to give a mixture of diastereomeric syn and anti diols which were then stereospecifically cyclized into the corresponding oxetanes with an overall yield for the two steps of 69.6%. The newly synthesized stereoisomeric four-membered oxygenated heterocycles were separated by column chromatography on silica gel and fully spectroscopically characterized.

A two-step stereoselective chemoenzymatic synthesis of optically active ?-aryl-substituted oxygen heterocycles was developed, exploiting a whole-cell mediated asymmetric reduction of ?-, ? -, and ? -chloroalkyl arylketones followed by a stereospecific cyclization of the corresponding chlorohydrins into the target heterocycles. Among the various whole cells screened (baker's yeast, Kluyveromyces marxianus CBS 6556, Saccharomyces cerevisiae CBS 7336, Lactobacillus reuteri DSM 20016), baker's yeast was the one providing the best yields and the highest enantiomeric ratios (up to 95:5 er) in the bioreduction of the above ketones. The obtained optically active chlorohydrins could be almost quantitatively cyclized in a basic medium into the corresponding ?-aryl-substituted cyclic ethers without any erosion of their enantiomeric integrity. In this respect, valuable, chiral non-racemic functionalized oxygen containing heterocycles (e.g., (S)-styrene oxide, (S)-2-phenyloxetane, (S)-2-phenyltetrahydrofuran), amenable to be further elaborated on, can be smoothly and successfully generated from their prochiral precursors.

A high-yield one-pot two-step synthesis of 2-aminoimidazoles (2-AI), exploiting an under-air heterocyclodehydration process between α-chloroketones and guanidine derivatives, and using deep eutectic solvents (DESs) as nonconventional, "green" and "innocent" reaction media, has been accomplished successfully. The combination of either glycerol or urea with choline chloride (ChCl) proved to be effective for decreasing the reaction time to about 4-6 h in contrast to the 10-12 h usually required for the same reaction run in toxic and volatile organic solvents and under an argon atmosphere. In addition, the use of the ChCl-urea as a DES also enables the direct isolation of triaryl-substituted 2-AI derivatives by means of a simple work-up procedure consisting in filtration and crystallization, and allows the recycle of the DES mixture. A plausible mechanism highlighting the potential role played by hydrogen bonding catalysis has also been illustrated.

A short and efficient synthesis of tetrahydroindenofuranones based on the Michael addition of ortho-lithiated aryloxiranes to alkylidene malonates followed by the nucleophilic oxirane ring-opening and subsequent lactonization is described. The methodology has been applied to the synthesis of a structural analogue of epipodophyllotoxins.

[reaction: see text] A stereoselective synthesis of 9,10-epoxy-1,6-dioxa-4,7-diazaspiro[4,5]decanes has been developed on the basis of the addition of beta-lithiated oxazolinyloxiranes to nitrones. Conversion of these spirocyclic derivatives into 4,5-epoxy-1,2-oxazin-6-ones and successively into alpha,beta-epoxy-gamma-amino acids, alpha-hydroxy-gamma-amino acids, and gamma-butyrolactams is described.

[structure: see text]. The lithiation reaction of cis- and trans-N-alkyl-2,3-diphenylaziridines has been investigated. While cis-diphenylaziridines do not undergo any lithiation upon treatment with organolithiums, the lithiation reaction of the trans counterparts is completely alpha-regioselective and the stereochemical course of the lithiation-trapping sequence is solvent dependent: inversion of configuration in coordinating solvents (THF or toluene/crown ether) and retention in hexane, ether, or toluene. The preparation of stereodefined functionalized N-alkyl-2,3-diphenylaziridines is described.

[reaction: see text] A stereoselective/stereospecific synthesis of polysubstituted tetrahydronaphthols based on the Michael addition of ortho-lithiated stilbene oxides to alpha,beta-unsaturated Fischer carbene complexes followed by an unusual cyclization of the corresponding intermediate in a 6-endo-tet mode is described.

A simple and efficient stereoselective synthesis of polysubstituted beta,gamma-epoxyhydroxylamines and 4-hydroxyalkyl-1,2-oxazetidines, based on the addition of alpha-lithiated aryloxiranes to nitrones and subsequent cyclization of the corresponding intermediates in a 4-exo-tet mode, is described.

[reaction: see text] The stereospecific alpha-lithiation of optically active styrene oxides and the trapping reaction of the corresponding highly reactive intermediates with electrophiles to produce optically active styrene oxide derivatives are described. This methodology has been applied to the synthesis of an optically active oral antifungal agent of industrial interest.

The addition of 2-(lithioalkyl)-4,5-dihydro-1,3-oxazoles 2a−c and 2-[chloro(lithio)alkyl]-4,5-dihydro-1,3-oxazoles 2d,e to nitrones 3 has been studied. While lithiated 2-methyl-4,5-dihydro-1,3-oxazole 2a adds stereoselectively to nitrones 3, resulting after long reaction times (3 h) in the formation of 2-[(E)-alkenyl]-4,5-dihydro-1,3-oxazoles 8a−h, lithiated 2-(chloromethyl)-4,5-dihydro-1,3-oxazole 2e affords 2-[(Z)-alkenyl]-4,5-dihydro-1,3-oxazoles 26a−d and 26f−h. α-Lithiated 2-ethyl-4,5-dihydro-1,3-oxazole 2b adds to 3a to give the 1,6-dioxa-2,9-diazaspiro[4.4]nonane 9 and 2-alkenyl-4,5-dihydro-1,3-oxazole 14 after treatment with oxalic acid. Quenching after short reaction times shows that the conversions of 2a to 8 and of 2b to 14 go through spirocyclic compounds 7 and 9, while the reaction between 2e and 3a, quenched even at short reaction times, gives a mixture of the 1,6-dioxa-2,9-diazaspiro[4.4]nonanes 21-H and 22-H and the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-oxazoles 25a and 27a. The addition of 2c to 3a furnishes the 1,6-dioxa-2,9-diazaspiro[4.4]nonane 15 and then isoxazolidin-5-one 16 upon hydrolysis with oxalic acid. The addition of 2d to 3a gives the 1,6-dioxa-2,9-diazaspiro[4.4]nonanes 17b and 18b after short reaction times and the 2-(1,2-oxazetidin-4-yl)-4,5-dihydro-1,3-oxazole 19 after long reaction times. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)

The oxazoline-derived titanium azaenolate 6 couples highly stereoselectively with aldehydes affording highly optically pure oxazolinyloxiranes 7. The epoxide 7a has been deblocked to form the optically pure formyl oxirane 9. In contrast, the corresponding boron azaenolates 2 and 3 couple with very poor or no stereoselectivity. Lithium, aluminum and tin azaenolates have also been shortly studied.